Synapses are intercellular junctions that mediate neuronal communication, and likely involve many cell-adhesion molecules that connect pre- and postsynaptic neurons to each other. Neurexins are presynaptic cell-adhesion molecules that are essential for the formation of functional synapses, and for the specification of the properties of synapses. Neurexins are highly polymorphic due to extensive alternative splicing, interact with multiple postsynaptic cell-adhesion molecules, and are associated with autism-spectrum disorders and schizophrenia, which highlights their importance for synaptic circuits. However, how exactly neurexins function in synapses, and how this function is impaired in autism spectrum disorders and schizophrenia, remains unclear. In the present application, we propose four specific aims to examine how neurexins function in synapses. These aims utilize a combination of mouse genetics, electrophysiology, biophysics, and protein chemistry to determine the general functions of different neurexin isoforms, to understand the biological significance of their alternative splicing, to characterize how neurexins interact with multifarious ligands in a tightly regulated manner, and to elucidate the specific significance of their interactions with various ligands. These experiments will provide a comprehensive exploration of neurexin function and the mechanisms involved in this function, and clarify how neurexins act in specifying synapse properties. The results of these studies will not only provide insight into synaptic function in general, but also advance our understanding of synaptic dysfunction in cognitive disorders such as autism and schizophrenia. PUBLIC HEALTH RELEVANCE: Synapses mediate the communication between nerve cells in brain, and are impaired in cognitive diseases such as autism or schizophrenia. Synapses are formed by cell-adhesion molecules such as neurexins, which in recent studies have been implicated in schizophrenia and autism. In the present project, we will continue our long-term investigation of how neurexins function at synapses, and how impairments of their function leads to cognitive diseases. Results from this project will not only provide insight into how neurons communicate, but also promote our understanding of how such communication becomes dysfunctional in autism and schizophrenia.